Current Pharmaceutical Strategies for the Long-Term Management of Addiction

Background: Substance use disorders (SUDs) are chronic, progressive brain diseases that result in continued liability to relapse, even after periods of abstinence. Objectives: This review synthesizes current evidence for a paradigm shift in addiction medicine: from suppression of acute drug effects to repair of the neurobiological substrates underlying relapse vulnerability. Method: We used medical databases to conduct an electronic search to identify the objectives. We reviewed in detail the existing pharmacotherapies for SUD, discussing their mechanisms of action, efficacy data, and limitations. We then reviewed novel drug classes that target resilience-promoting mechanisms to conclude a comprehensive roadmap for the management of addiction. Result: Novel drug classes that target resilience-promoting mechanisms, including GLP-1 receptor agonists that modulate mesolimbic dopamine signaling, orexin receptor antagonists that target stress-induced craving, kappa-opioid receptor antagonists that counteract stress-induced dysphoria, and corticotropin-releasing factor (CRF) antagonists that normalize hypothalamic–pituitary–adrenal (HPA) axis dysfunction. Furthermore, agents that stimulate neuroplasticity (ibogaine, noribogaine, glutamate modulators) and agents that target neuroinflammation (endocannabinoid modulators, microglial inhibitors), and biological interventions, including immunopharmacotherapy and psychedelic-assisted therapies, are new strategies for long-term management of addiction. Conclusions: Long-term management of addiction should provide a comprehensive roadmap to the development of next-generation addiction therapeutics that restore neural circuit function and promote long-lasting resilience to relapse for medicinal chemists and neuroscientists.